About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

June 6, 2008

Resveratrol in Mice

Posted by Derek

Since it’s a favorite topic of mine, I really have to point out this study in PLoS ONE on resveratrol. A large collaboration looked at the gene transcription effects of dosing the compound in mice, compared to a normal diet and to a calorie-restricted one. I can’t do better than the first paragraph of the paper does at setting the scene:

” Caloric restriction (CR) retards several aspects of the aging process in mammals, including age-related mortality, tumorigenesis, physiological decline and the establishment of age-related transcriptional profiles. The wide scope of these actions, and the profound metabolic and hormonal shifts induced by CR has led to efforts at identifying natural or synthetic compounds that mimic the effects of CR in the absence of overt metabolic and endocrine disturbances or reduced caloric intake. Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan.”

That’s a fine list of things that everyone would like to avoid: cancer, decline, and death. And the last sentence makes a key point, that the age-related diseases are not inevitable, but can be attacked as a group by attacking aging itself. A few years back, that statement might not have made it into a scientific paper at this level, but it can now.

This study had three groups of male mice (in a hybrid strain derived from C57 black): a control group getting 84 kcal/mouse/week of food, a calorie-restricted group getting 25% less chow, and a group getting the first diet plus 4.9 mg/kg of resveratrol, both experimental diets starting at mouse middle age (14 months). This same group had already reported that starting CR at that point in that mouse strain leads to about a 13% increase in lifespan.

As a baseline, they checked the transcriptional changes in young versus old mice on the control diet. There were, for example, about a thousand genes in heart tissue (out of twenty thousand checked) with a highly significant change in their profile. Comparing old heart tissue from the controls to the old tissue from the CR group, 536 genes showed a highly significant difference due to caloric restriction. The resveratrol-treated group, meanwhile, showed the same level of change in 522 genes, from basically the same list.

They also looked at skeletal muscle and brain (neocortex) and found similar but definitely less dramatic effects. In muscle, CR only affected about a quarter of the age-related genes (as opposed to half in the heart), and resveratrol was very similar. In the brain tissue, CR was able to reverse the aging profile in only 19% of age-related genes, and resveratrol lagged with 13%. The take-home message there is that aging can be a different process in different tissues, and attempts to alter it are going to vary across those tissues as well. (Here's the figure covering all these).

Another interesting question is whether CR (or resveratrol) affect other genes that aren’t in the age-related group. The answer is “Oh, yes indeed”, with over seven hundred genes whose profile was altered by CR but are not directly altered by age alone. (Compare that to the thousand age-altered genes, five hundred of which are reversed by CR, and you can see that this could be a source of significant effects). Resveratrol treatment did an extraordinary job of mimicking this profile, affecting 745 of the same 747 genes. The same thing was found in the other tissues – 1164 non-age-related transcription changes were found in skeletal muscle from the CR mice, and resveratrol treatment affected all 1164 of them.

So resveratrol appears to be a pretty close mimic of caloric restriction – but it’s closest in the non-age-related genes, which is interesting. The thing is, there’s no guarantee that all these transcriptional changes are good – presumably a lot of the ones that reverse age-related changes are beneficial (although we don’t know that for sure), but the ones that aren’t involved in aging could be more of a mixed bag. The net effect of CR does seem to be beneficial, but there are a lot of ways to arrive at that end point, and resveratrol could be mimicking the bad as well as the good. Here’s an attempt at figuring out the functions of the various genes involved in each group.

Of course, a much more relevant measure of benefit is how the animals themselves are doing under these treatments. The paper looks at some measures of cardiac function in young and old control mice, as well as in the treatment groups, and find that both CR and resveratrol seem to protect against decline. That chart also shows some other physiological readouts, at least one of which is rather surprising.

There's a huge insulin-signaling component in this whole field of study - the putative target of resveratrol (the sirtuins) are thoroughly tangled up in insulin and insulin-related growth factor (IGF) pathways. Genetic manipulation of several genes in those areas has also shown powerful effects on lifespan and aging in model organisms. So one of the oddities here is that the CR diet showed an effect on IGF-1, but resveratrol didn't. And while both treatment groups showed increased insulin sensitivity, several markers of that (glucose transporters, for example) showed the expected changes in the CR group but not the resveratrol group.

So if resveratrol treatment really does increase lifespan in the same way that caloric restriction does, it could mean that the insulin signaling axis isn't as important in CR as people thought. That's a difficult conclusion to come to, given the other data in the field, so a more reasonable one might be that resveratrol is hitting those same pathways, but not in the same way that CR does. (The similar increase in insulin sensitivity in the two groups argues for that view). Supporting this view, the transcription factor Pgc-1alpha, which is known to be very important for a range of genes in insulin sensitivity, was upregulated in muscle in the CR group but untouched in the resveratrol group.

The weirdest thing about this whole study, though, to my mind was the finding that levels of the prototype sirtuin, SIRT1, were not elevated in either group. That's in direct contrast to results seen in rats and humans under caloric restriction. In fact, in this case SIRT1 levels actually went down in the CR mice. There are several potential conclusions, all of which will keep people busy for a good while: perhaps some (or most?) of the anti-aging benefits of either CR or resveratrol in all species are coming from something else other than the effect on SIRT1. That would sow confusion, for sure. Or perhaps this is only true in mice, but not in rats (or people), and the sirtuin pathway really is the answer in the other species - in that case, you have to wonder what's so special about mice, and just what those different pathways are that kick in with them.

No, this is a very interesting study, and a very hopeful one, but it also points out just how much we don't know. I'm sure many more surprises like this are on the way, both positive and negative ones. But the overall point is made: aging and its effects can be altered. We don't understand quite how it's happening, and there are a lot of things to be worked out, but we can do it. If we can get the details worked out, human history is going to go through the biggest inflection point since fire and agriculture.

This is all well and good for mice, but does anyone have any data on the effects of CR on humans? I know that some people in the States are trying on themselves, but the historical data (life expectancy in Bangladesh, for example) don't look too encouraging.

And at the same time resources are getting more and more limited. It sounds cynical, but wouldn't it be better for our planet to reduce the human population a little bit? There are simply too many of us and preventing us from aging is probably not the best solution. But, as we know, money has the highest priority in our lifes. Probably evolution has to produce another human being in order to change this. At some day the flu or some other quickly spreading disesase might help us shifting our priorities back to reality again.

Resveratrol can help you to lead a long and healthy life so says Dr. Oz.

Resveratrol Supplements can help you control your weight naturally
by increasing energy, reducing cravings, and limiting your appetite.
According to Wikipedia, Consumer Lab, an independent dietary
supplement and over the counter products evaluation organization,
published a report on 13 November 2007 on the popular resveratrol
supplements. The organization reported that there exists a wide range
in quality, dose, and price among the 13 resveratrol products
evaluated. The actual amount of resveratrol contained in the
different brands range from 2.2mg for Revatrol, which claimed to have
400mg of "Red Wine Grape Complex", to 500mg for Biotivia.com Transmax,
which is consistent with the amount claimed on the product's label.
Prices per 100mg of resveratrol ranged from less than $.30 for
products made by Biotivia.com, jarrow, and country life, to a high of
$45.27 for the Revatrol brand. None of the products tested were found
to have significant levels of heavy metals or other contaminants.

I have been taking Bioforte from Biotivia.com for over 1 year now
and have felt a great increase in my stamina and endurance levels
and my normal aging aches and pains have almost gone.
I fortnately had no major problems with my health before taking Bioforte,
but nevertheless realised that maybe because I was in my fifties that I should
cut back in some of my hobbies which include cycling and running my own business (Stress!!)
I now have a fantastic outlook on my future which I put down to Resveratrol.
Maybe I can have a fantastic finish to my life and not have to retire to an old age pensioners
home after all!
All you guys out there should look into this as lots and lots of retired Doctors are taking this as we speak.
If it works for them then why not you?
I now look forward to a bright future with aging not being on my agenda.
It`s worth a look at as the prices are really low and available to people on a tight income
just like myself.
Lots of my friends are waking up to this new idea and are now beginning to try resveratrol
for lots of ailments they have.
I look forward to see how they how many of them see improvements in themselves.
One of my closest friends has Diabetes, and as the results coming through on the web are very optimistic
I will be keen to know if this helps him as he will be able to tell from his blood diagnosis really
quickly if the resveratrol is working for him.
The products from Biotivia seem to be the best on the market that I have found, but please do a little research
for yourself before you buy.
This could change your life for the better.

It's Sunday morning in America. All around this great land people are giving testimony about the health of their soul. They don't call it science. Your comment fits into this genre.

It's good that you feel better on the product. But have a look at comment #2 on the May 6 post "Alzheimer's: A report from the front" here for the long, sad story of postmenopausal supplemental hormones and what they did to the people taking them.

They had a lot more than theory and animal experimentation to back them up -- over 50 observational studies in people showed benefit. Caveat Emptor.

I've always been a little skeptical about this. The study is great, but in my opinion, resveratrol is sort of a black box still to many medicinal chemists, and many discount it and bin it in with the chalcones/xanthones/flavones/other natural products that are "good for you but nobody's sure why."

I knew a girl who was making resveratrol analogues to investigate their chemopreventive effects, and she claimed making the analogues was a "synthetic nightmare," as resveratrols are extremely polar and difficult to separate from organic salts. She also had migratig protecting groups and all sorts of other nastiness.

I'm somewhat ambivalent on the implications for humans. Mice are something of the worst case scenario for aging and I would be willing to wager a much greater genetic "planned obsolescence" factor in mice than in humans, where simple wear and tear is likelier to play a larger role than undesirable gene expression.

Still, this is a nice paper and they've taken the mouse model about as far as it can go. The echos were a nice touch.

"I'm somewhat ambivalent on the implications for humans. Mice are something of the worst case scenario for aging and I would be willing to wager a much greater genetic "planned obsolescence" factor in mice than in humans, where simple wear and tear is likelier to play a larger role than undesirable gene expression."

This truly is a nice paper, and I'm not exactly sure if Bob had it right. I know that mice are (obviously) different than humans, but, I really feel like its just a matter of time before we hammer out these details revolving around resveratrol use.

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